Cysteine proteases, such as cathepsins B, H, L, S, and O.sub.2, play a central role in a broad spectrum of medical disorders. Under normal condition, cysteine proteases function in a variety of biological processes including cell differentiation, platelet aggregation, cell invasiveness, post ribosomal processing of proteins and protein turnover. However, when cysteine proteases are deregulated in abnormal conditions, they have been implicated in a variety of diseases. Abnormal activities of lysosomal cysteine proteases have been implicated in the development and progression of a variety of human diseases, due to their ability to degrade components of extracellular matrix. Some of these diseases are cancer metastasis and invasion (Clin. Exp. Metastasis 1992, 10, 145-155; cancer metastasis rev. 1990, 9, 333-352), rheumatoid arthritis (Int. J. Biochem. 1993, 25, 545-550; Arthritis Rheumatism 1994, 37, 236-247; J Rheumatol. 1993, 20, 1176-1183; Biochem. Pharmacol. 1993, 44, 1201-1207), muscular dystrophy (Am. J. Pathol. 1986, 122, 193-198; 1987, 127, 461-466), myocardial infarction (J. Am. Coll. Cardiol. 1983, 2, 681-688), viral and parasitic infection (Rev. Infect. Dis., 1983, 5, 5914-5921) and common cold (Biochem. 1995, 34, 8172-8179).
The calcium-associated cysteine proteases calpains I and II have been associated with osteoporosis, ischemia and hypoxia, Alzheimer's disease (Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 2628-2632) and cataracts (J. Biol. Chem. 1993, 268, 1937-1940).
Cathepsin B and L have been shown to have the ability to degrade type IV collagen, laminin, fibronectin, and elastin (the components of extracellular matrix), at both acidic and neutral pH. (Annual Reports in Medicinal Chemistry, 1993, pp. 141-160; Protease Inhibitors as Cancer Chemopreventative Agents, 1993, pp. 199-216; Eur. J. Clin. Chem. Clin. Biochem., 30: 69-74, 1992). Their consistently increased levels in many malignant cancers makes them a perfect candidate for use in the diagnostic area or in prognosis for the progression of the cancer. Elevated levels of Cathespin L and B have been found in kidney, testicular, colon, breast, lung, bladder and ovarian cancer patients. (Eur. J. Clin. Chem. Clin. Biochem., 30: 69-74, 1992; Med. Sci. Res., 22: 31-32, 1994; The Journal of Urology, 144: 798-804, 1990; Neoplasma, 37.1:61-71, 1990; Cancer Research, 51: 1137-1142, 1991; Cancer, 74: 46-51, 1994). In addition, the expression of these enzymes correlates with tumor progression and shortened patient survival, in which a high level of Cathespin B was very indicative of a significantly shorter survival rate. (American Journal of Pathology, 145.2: 301-309, 1994; Cancer Research, 52: 3610-3614, 1992). It is clear that cysteine proteases are, therefore, excellent targets for the development of specific inhibitors as possible therapeutic agents.
Several types of cysteine proteases inhibitors have been reported, such as peptide aldehyde (Biochem.. Biophys. Acta 1991, 1073-43), nitrites (Biochem.. Biophys. Acta 1990, 1035, 62-70), halomethyl ketones (Anal. Biochem. 1985, 149, 461-465; Acta. Biol. Med.Ger. 1981, 40, 1503-1511; Biochem. Phar. 1992, 44, 1201-1207), (Biochem. J. 1988, 253, 751), acyloxy methyl ketones (J. Med. Chem. 1994, 37, 1833-1840; J. Am. Chem. Soc. 1988, 110, 4429-4431), ketomethylsulfonium salt (J. Biol. Chem. 1988, 263, 2768-2772), .alpha.-ketocarbonyl compounds (J. Med. Chem. 1993, 36, 3472-3480; 1994, 37, 2918-2929), vinyl sulfones (J. Med. Chem. 1995, 38, 3193-3196), and epoxysuccinyl derivatives (Agric. Biol. Chem. 1978, 42, 523-527). These inhibitors, in general, have a peptidyl affinity group and a group reactive towards the thiol of the cysteine residue in cysteine proteases. Some of them are clinically useful. However, the efficacy in vivo is not as much as expected on the basis of in vitro inhibitory activity and may be due to lower selectivity towards other proteases and poor pharmacokinetics. There exists a continuing need to develop new low molecular weight, nonpeptidyl cysteine proteases inhibitors with high selectivity, lower toxicity and better pharmacokinetics.
In continuation of work done related to .beta.-lactam skeleton containing compounds for the use of .beta.-lactamase inhibitor (U.S. Pat. No. 4,562,073, J.Med.Chem. 1987, 30, 1469), elastase inhibitor (U.S. Pat. No. 5,264,429,1993; U.S. Pat. No. 5,264,430,1993; U.S. Pat. No. 5,258,377,1993; U.S. Pat. No. 5,446,037,1995 and U.S. Pat. No. 5,439,904,1995), anticancer activity (WO 94/01109, PCT/GB95/00023, PCT/GB95/00024) and cysteine protease inhibitor, we have screened certain low molecular weight .beta.-lactam class of compounds for cysteine protease inhibitory activity and the use of such compounds as cysteine protease inhibitor are reported in the present invention.